Production of clavulanic acid by genetic engineering of Streptomyces clavuligerus

Abstract

Genetically engineered Streptomyces clavuligerus strains with improved capabilities to produce clavulanic acid are provided. The strains are genetically engineered by disrupting newly identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes. This results in an increased intracelluar pool of the clavulanic acid precursor D-glyceraldehyde-3-phosphate (D-G3P), and increased clavulanic acid production. Clavulanic acid production may be further increased by supplying arginine to the medium in which the S. clavuligerus is grown.

1.  Streptomyces clavuligerus  genetically modified such that a nucleic acid sequence encoding the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of SEQ ID NO: 43 is deleted or mutated so that GAPDH activity is missing or reduced, or progeny thereof. 
     
     
       2. The  Streptomyces clavuligerus  of  claim 1 , wherein said nucleic acid sequence encoding a GAPDH enzyme is SEQ ID NO: 50.